P636: A FIRST-IN-HUMAN PHASE 1 STUDY OF ORAL LOXO-338, A SELECTIVE BCL2 INHIBITOR, IN PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES
Authors: Michal Kwiatek, Guru Subramanian Guru Murthy, Marc Hoffmann, Lindsey Roeker, Benoit Tessoulin, Alexey Danilov, Alvaro J. Alencar, Nirav N. Shah, Herve Ghesquieres, Steven Le Gouill, Wojciech Jurczak, Anthony R. Mato, Vishalkumar Patel, Yingying Guo-Avrutin, James M. Pauff, Maciej Kazmierczak
Journal: HemaSphere (2023)

Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematological malignancies. LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor (Brandhuber B. et al. 2021 Cancer Research 81 (13 Suppl) 1258). Aims: To determine the recommended phase 2 dose (RP2D) of LOXO-338 and evaluate the safety and antitumor activity of LOXO-338 monotherapy. Results from the dose escalation part of LOXO-338 monotherapy are reported here. Methods: LOXO-BCL-20001 is a global, open-label, multi-center, first-in-human phase 1 study of oral LOXO-338 in patients with advanced hematologic malignancies who had received standard therapy (NCT05024045). Dose escalation followed an i3 + 3 design and evaluated LOXO-338 as monotherapy in a flat-dose schedule. Each cycle was 28 days (4 weeks). Eligible patients included those with CLL/SLL, mantle cell lymphoma (MCL), and Waldenstrӧm macroglobulinemia (WM) who had relapsed or refractory disease after 2 or more lines of prior therapy. Patients with other B-cell non-Hodgkin lymphomas (NHL) including follicular lymphoma (FL) and marginal zone lymphoma (MZL) who had no known available options to provide benefit for the patient’s condition were also eligible. Patients must not have progressed while receiving a prior BCL2 inhibitor; those with WM must not have received a prior BCL2 inhibitor. Key exclusion criteria included history of CNS involvement, and stem cell transplant or CAR-T therapy within 60 days. The primary objective of dose escalation was to determine the RP2D of LOXO-338 monotherapy in patients with CLL/SLL and other B-cell NHL. Determining antitumor activity in patients with WM was an additional primary objective. Secondary objectives included determining the safety profile, PK properties, and antitumor activity of LOXO-338 based on disease-specific response criteria per investigator assessment. Results: As of 18 October 2022, 22 patients with CLL/SLL (8), FL (6), MCL (3), MZL (3), and WM (2) were treated with LOXO-338 on doses ranging from 50-300 mg QD. Patients were median 68 years of age (range, 48-81) with a median of 3 prior therapies (range, 2-8). 68% of patients had received a prior BTK inhibitor, and none had received a prior BCL2 therapy. Median time on treatment was 2.4 months (range, 0.5-7), 16 patients are ongoing, and 6 patients discontinued (none due to a related AE). No DLTs were observed and MTD was not reached. TEAE observed in ≥10% of patients were fatigue (14%) and night sweats (14%), mostly grade 1 or 2, and anemia (14%), all grade 3. Tumor lysis syndrome was not observed. There were no treatment related serious AEs or deaths. Of the 8 patients with CLL/SLL, 2 had PR, 3 had SD, and 3 were not evaluable. Among the 14 NHL/WM patients, there were 4 SD, 3 PD, and 7 were not evaluable. Updated data will be presented at the meeting. Summary/Conclusion: LOXO-338 demonstrated a favorable safety profile and was well tolerated at tested dose levels. Preliminary efficacy was observed with LOXO-338 monotherapy in patients with CLL/SLL. Keywords: BCL2, B-CLL, Waldenstrom’s macroglobulinemia, B cell lymphoma